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Abstract

Pulmonary alveolar proteinosis (PAP) is a rare disease caused by the accumulation of surfactant proteins and lipids in the pulmonary alveoli resulting in respiratory distress. For almost all reported cases the underlying cause is unknown. Synthesis and secretion of surfactant in the lung is restricted to epithelial type 2 pneumocytes (T2 cells). However, subsequent clearance of surfactant from the hypophase is dependent upon both T2 cells and macrophages. Both T2 cells and macrophages express high levels of the sterol-transporter ATP Binding Cassette transporter G1 (ABCG1). Further, Abcg1-/- mice exhibit a severe pulmonary lipidosis, characterized by elevated levels of multiple lipid species and the presence of lipid-loaded macrophages and T2 cells containing abnormal lamellar bodies. Recent advances have implicated a role for specific granulocyte-macrophage colony stimulating factor (GM-CSF) autoantibodies and the innate immune system in the pathogenesis of PAP. We have recently demonstrated that the lungs of Abcg1-/- mice accumulate specific oxidized phospholipids and that this is associated with a local increase in innate immune natural antibody-secreting B-1 B cells and both local and circulating natural antibodies. Here we show that the lungs of mice containing ABCG1-deficient T2 (T2KO) cells and wild-type macrophages contain elevated levels of both phospholipids and esterified cholesterol. In addition, the T2KO cells in these mice accumulated lamellae bodies, unesterified cholesterol and exhibited abnormal gene expression. Collectively, our results suggest that ABCG1 is critical for normal surfactant metabolism and that the pulmonary expansion of B-1 B cells and the subsequent increase in natural antibodies in Abcg1-/- mice may provide a novel model in which to study the role of the innate immune system in PAP.